Animal models serve as practical tools in studying various human diseases and are necessary to investigate and design appropriate interventions. However, HIV is a human-specific pathogen. This restriction prevents the use of traditional mouse models for research as mice cannot become infected with the virus. We currently have traditional NRG humanized mice that express human HLA molecules which leads to increased immune reconstitution, more functional T cell subsets and isotype switched antibody production as well as other mice that support the development of human NK cells. There is wide applicability of these models for both understanding disease pathogenesis and developing/testing therapeutics and vaccines.